US5629018A - Composition for controlled release of an active substance and method for the preparation of such a composition - Google Patents
Composition for controlled release of an active substance and method for the preparation of such a composition Download PDFInfo
- Publication number
- US5629018A US5629018A US08/362,442 US36244295A US5629018A US 5629018 A US5629018 A US 5629018A US 36244295 A US36244295 A US 36244295A US 5629018 A US5629018 A US 5629018A
- Authority
- US
- United States
- Prior art keywords
- glucan
- active substance
- composition
- weight
- composition according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
Definitions
- the invention relates to a composition for delayed release of an active substance in a target environment, the active substance being incorporated in a polysaccharide matrix.
- compositions for delayed release of an active substance for example for delayed release of an enzyme for oral administration in the gastrointestinal tract of a mammal, have advantages, inter alia because the administration of the active substance can take place in a small number of doses and because a more constant concentration is obtained in the target environment.
- compositions for delayed release are known in diverse forms.
- One form of delayed release can comprise the presence of a matrix containing the active substance therein, which matrix slowly dissolves in the aqueous environment and thus releases the active substance in a delayed manner; a composition of this type is, for example, disclosed in European Patent Application EP-A-241179.
- a composition of this type in which the matrix is formed by a natural polysaccharide such as xanthan is disclosed in International Patent Application WO-A-87,05212.
- the active substance is packaged in an insoluble capsule which is provided with a water-soluble stopper, as disclosed, inter alia, in British Patent Application 2,241,485.
- compositions for delayed release are compositions from which the active substance is released by erosion, as is disclosed, for example, in European Patent Application EP-A-381182.
- a ⁇ -glucan such as cellulose or a cellulose derivative
- the known compositions for the delayed release of an active substance frequently have the disadvantage that release is possible only for substances dissolving in the environment or effectively diffusing through the matrix material. Furthermore, the active substance of the known compositions does not normally proceed in accordance with an ideal zero order rate, that is to say with a constant amount per unit time, but in accordance with a first order rate, that is to say with an amount which decreases per unit time, or poorer; in addition, the materials used as matrix are often expensive.
- the object of the invention is to provide a composition, and a method for the preparation thereof, which releases an active substance in a delayed manner and within a predetermined period of time, which further is harmless to health and/or the environment and which, moreover, is economical in use.
- the composition should especially be suitable for delayed release of active substances having a high molecular weight, which moreover are sensitive under certain conditions, such as a low pH or at increased environment temperatures.
- composition according to the invention which to this end is characterised in that the matrix material in which the active substance is incorporated comprises an essentially crystalline straight-chain glucan and a glucan-degrading agent.
- the glucan is preferably an ⁇ -glucan and in particular an ⁇ -1,4-glucan and preferably has essentially a helical structure.
- ⁇ -1,4-glucan is understood to be an essentially straight-chain polysaccharide which is composed of anhydroglucose units which are linked to one another by ⁇ -bridges via the 1-position and 4-position.
- Other straight-chain glucans can also be used if these are able to assume a spiral-like structure, such as, for example, ⁇ -1,3-glucans.
- Suitable ⁇ -1,4-glucans are in general starch fractions and starch derivatives.
- the ⁇ -1,4-glucan can, for example, be an amylose.
- Amylose is a straight chain of ⁇ -1,4-anhydroglucose units which has a degree of polymerisation (DP) of the order of 100-1,000.
- DP degree of polymerisation
- amylose V Avebe
- amylose V an amylose which has an amorphous structure and is precipitated from an aqueous solution by magnesium sulphate.
- This so-called helical amylose or crystalline amylose can be obtained from amylose by dissolving in water and complexing with a complex-forming agent such as 1-butanol, after which the complex-forming agent can be removed by careful spray-drying or by treatment with a suitable solvent, such as ethanol, methanol or acetone.
- a suitable solvent such as ethanol, methanol or acetone.
- the crystalline and/or helical amylose to be used in the compositions according to the invention can also be obtained directly from starch, in a similar process using a complexing agent, further including washing the complex to remove amylopectin.
- Suitable complexing agents for preparing crystalline, helical amylose by precipitating amylose from an aqueous solution include 1,1,2,2-tetrachloroethane, cyclohexane, 1,1,1-and 1,1,2-trichloroethane, benzene, chloroform, fluorobenzene, o-xylene, 2,3-dimethylbutane, C 3 -C 8 alcohols and phenols, such as butanol, amyl alcohol, cyclohexanol, hexanol and 2-octanol, isopropyl ketone, quinoline, chloral hydrate, butyric acid etc. See e.g. J. Muetgeert, Advances in Carbohydrate Chemistry, Vol. 16 Ed. Melville, Wolfrom, Acad. Press (1961).
- Derivatives which are obtained by debranching branched glucans, in particular amylopectins, are also suitable.
- the ⁇ -1,6 bonds of amylopectin are broken, preferably enzymatically (see Kobayashi, S. et al., Cereal Chem. 63, 71-74 (1968) and Netherlands patent 160,615) with the formation of amylodextrin, a straight-chain dextrin.
- This has a chain length (DP) of the order of 15-75, with a maximum between 15 and 25 and a maximum between 45 and 75.
- Amylodextrin like the amylose V helix, occurs in the helix form with approximately 6 to 7 anhydroglucose units per winding.
- the crystalline ⁇ -1,4-glucans suitable for use in the present compositions can be distinguished from unsuitable types of glucans by their infrared spctrum.
- the crystalline amylose and amylodextrin, just like cyclodextrin, have sharp absorptions at about 1150, 1080 and 1020 cm -1 , whereas amorphous amylose only exhibits broad or undistinguished absorptions at these frequencies.
- the glucan-degrading agent is chosen as a function of the intended use of the composition. If used for release in the digestive tract of mammals, including man, the degrading agent is preferably an amylase and in particular ⁇ -amylase, an enzyme which normally cleaves starch.
- the composition can pass the acid conditions of the stomach without hindrance, whereafter, under more neutral conditions, the glucan is degraded and the active substance is gradually released.
- tablets and other administration forms which comprise such crystalline straight-chain glucans as matrix-forming material in combination with a glucan-degrading agent, are subject to little or no disintegration under certain conditions and can still disintegrate under other conditions. It is also surprising that the administration forms suffer little or no attack by externally present ⁇ -amylase, for example in the gullet, or by acid either. In addition, the tablets are found to be resistant to breaking and often more resistant to breaking than microcrystalline cellulose (for example Avicel®).
- microcrystalline cellulose for example Avicel®
- the matrix material contains at least 5% by weight of water. If the material contains less than 5% of water, a usable release pattern is obtained but the strength is then no better than that, or even worse than that, of microcrystalline cellulose. Preferably, the material contains no more than 25% by weight, and more preferably no more than 20% by weight of water. In particular, the matrix material contains 7-16% by weight of water.
- the matrix material can contain other fillers and auxiliaries.
- the presence of amylose not having a helix structure up to a content of, for example, 40% by weight does not interfere.
- Many types of starch contain about 25% of amylose and this therefore does not have to be removed if the starch is used as starting material for the matrix-forming material.
- Usable auxiliaries are the auxiliaries known per se for compositions of active substances, such as lubricants, for example magnesium stearate, co-solvents, pH regulators, preservatives, disintegrating agents, colorants, flavourings and the like.
- auxiliaries which modify the release pattern of the active substance from the matrix such as auxiliaries which in themselves are inactive, for example lactose, can also advantageously be present.
- the active substance can be present in the matrix material in virtually any desired concentration.
- the chosen concentration is largely determined by the intended use and the type of active substance. Thus, low concentration will suffice in many instances in case of enzymes.
- the amount of active substance can make up, for example, 0.01-80% by weight of the composition, partly depending on the desired dosage. More particularly, the amount is between 0.05 and 25% by weight. Within this range, a release rate is obtained which is independent of the remaining amount of active substance, that is to say which has a zero order curve at least during the first part of the release period, example for 4 to 6 hours. This is also an unexpected aspect of the compositions according to the invention.
- the rate of release of the composition according to the invention can be adjusted by varying one or more of the following parameters: active substance concentration in the matrix material, dosage unit form, in particular the surface area/capacity ratio, force under which the composition has been pressed, concentration of the glucan-degrading agent, or presence of disintegration-retarding agents, such as a coating or an inert filler.
- the active substance can be of diverse natures. Examples are medicaments for oral, rectal, vaginal or transdermal administration, diagnostic agents, feedstuffs or conditioning agents, flavourings, manure or nutrients to be added to water or soil, preservatives, vaccine substances, hormones, genetic material, pesticides, attractants, growth promoters and the like.
- the active substances are also understood to comprise microorganisms, such as yeasts, moulds, bacteria and viruses and derivatives thereof. Mixtures of active substance can also be administered by means of the composition according to the invention. Release can take place in an aqueous medium, such as the gastrointestinal tract of animals, or in plants or in the soil.
- composition according to the invention is suitable, in particular, for the controlled release of substances of high molecular weight, such as more than 1,000 dalton, particularly more than 1,500 dalton, or even more than 5,000 dalton, and, in addition, substances which are poorly soluble in water.
- substances of high molecular weight such as more than 1,000 dalton, particularly more than 1,500 dalton, or even more than 5,000 dalton
- proteins such as enzymes, allergens, vaccine substances and oligosaccharides.
- composition can also be provided with a coating which ensures provides further protection or further delay of the release or, for example, has a colouring or taste function.
- the composition can also be in the form of a capsule in which the matrix material containing active substance is present, for example in granular form or powder form.
- composition according to the invention can be in any desired form, such as tablets, powders, granules, and implants.
- Tablets can be pressed directly after mixing the active substance with the crystalline glucan as matrix material and any other auxiliaries. Preferably, however, the mixture is granulated before or after physical mixing of the active substance and matrix material and is then tableted.
- the active substance can pass the acid conditions of, for example, the stomach, before the substance is released to the human or animal intestinal system.
- a physical mixture of amylodextrin and ⁇ -amylase (Dexlo P®) was prepared in a round-bottomed flask by stirring for 20 minutes.
- the amylase concentration was 0.5 and 2.0 wt. %.
- a blank (without amylase) was also prepared. Tablets having a weight of 300 mg, a diameter of 13 mm and a surface of 1.3 cm 2 were pressed from the mixture using a pressing force of 50 kN during 5 minutes. Erosion of the tablets was determined in an conical flask containing 50 ml of PBS (phosphate-buffered saline) of pH 7.0. After agitating at ambient temperature for 18 hours (150 rpm), the blank tablet was hardly eroded, the tablet containing 0.5% of amylase was eroded for about 75% and the tablet containing 2.0% of amylase was completely eroded.
- PBS phosphate-buffered saline
- a physical mixture of amylodextrin and enzymes (Dexlo P®) was prepared in a round-bottomed flask by stirring for 20 minutes. Tablets having a weight of 300 mg, a diameter of 13 mm and a surface of 1.3 cm 2 were pressed from the mixture using a pressing force of 100 kN during 10 minutes.
- the tablets of 300 mg had the following compositions:
- Xylanase substrate xylan, reducing sugar, according to Nelson-Somogyi (see above);
- Glucose Oxidase of Phanerochaete chrysosporium from Methods in Enzymology V161, Biomass Part B, Academic Press, New York, 1988.
- Tablets with 66 mg of cellulase and 15 mg of xylanase respectively were pressed at 100 kN/10 minutes following the procedure of Example II.
- the release pattern was determined in the manner mentioned in Example II: (a) directly at pH 7.0 and (b) at pH 7.0 after incubation for one hour at pH 2.0.
- the change of activity, measured from the reducing power, of the cellulase tablet is shown in table 5, and of the xylanase tablet in table 6.
- Tablets of 600 mg containing 1 mg of yeast cells (Saccharomyces cerevisiae, 10 7 cells per tablet) in amylodextrin/ ⁇ -amylase were pressed using a force of 5 kN during 20 sec. according to Example II.
- the tablets were given different pretreatments and were subsequently brought in an aqueous phosphate buffer having pH 7. At this pH, the tablets disintegrate after 1 hour, releasing the yeast cells.
- the viability was checked by counting the colony forming units (cfu). The results are summarised in table 7.
- Table 7 shows that the tablets prepared according to the invention are resistant to both heat and acid for some time; the acid treatment simulates a passage through the stomach. Disintegration of the tablet at neutral pH releases viable cells.
- metastable form (so-called because the amylose in this form is temporarily soluble in cold water) is obtained by removing the ethanol in vacuo (1 mm Hg) at 50° C. in the presence of phosphorus pentaoxide.
- amylose is chosen as raw material the washing steps needed to remove the amylopectin may be omitted. For the remainder, the procedure is similar as described above.
- complexing agent critical concentration in g per 100 ml of water
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Zoology (AREA)
- Botany (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NL9201196 | 1992-07-03 | ||
NL9201196A NL9201196A (nl) | 1992-07-03 | 1992-07-03 | Preparaat voor de gereguleerde afgifte van een werkzame stof en werkwijze ter bereiding van een dergelijk preparaat. |
PCT/NL1993/000138 WO1994001091A1 (en) | 1992-07-03 | 1993-07-02 | Composition for controlled release of an active substance and method for the preparation of such a composition |
Publications (1)
Publication Number | Publication Date |
---|---|
US5629018A true US5629018A (en) | 1997-05-13 |
Family
ID=19861015
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/362,442 Expired - Fee Related US5629018A (en) | 1992-07-03 | 1993-07-02 | Composition for controlled release of an active substance and method for the preparation of such a composition |
Country Status (12)
Country | Link |
---|---|
US (1) | US5629018A (nl) |
EP (1) | EP0648115B1 (nl) |
JP (1) | JPH07508532A (nl) |
AT (1) | ATE145821T1 (nl) |
AU (1) | AU677591B2 (nl) |
CA (1) | CA2139493A1 (nl) |
DE (1) | DE69306390T2 (nl) |
DK (1) | DK0648115T3 (nl) |
ES (1) | ES2096934T3 (nl) |
GR (1) | GR3022646T3 (nl) |
NL (1) | NL9201196A (nl) |
WO (1) | WO1994001091A1 (nl) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5885615A (en) * | 1996-04-10 | 1999-03-23 | Labopharm Inc. | Pharmaceutical controlled release tablets containing a carrier made of cross-linked amylose and hydroxypropylmethylcellulose |
US20030117171A1 (en) * | 2001-12-20 | 2003-06-26 | Fujitsu Limited | Input/output buffer circuit |
US20030215561A1 (en) * | 2002-05-14 | 2003-11-20 | Yong-Cheng Shi | Resistant starch prepared by isoamylase debranching of low amylose starch |
US20030215562A1 (en) * | 2002-05-14 | 2003-11-20 | Yong-Cheng Shi | Slowly digestible starch product |
US20030219520A1 (en) * | 2002-05-14 | 2003-11-27 | Yong-Cheng Shi | Slowly digestible starch product |
US20050033157A1 (en) * | 2003-07-25 | 2005-02-10 | Klein Dean A. | Multi-modality marking material and method |
US20070071810A1 (en) * | 2003-08-26 | 2007-03-29 | Kenichi Kudo | Additive for tablets |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19737481A1 (de) * | 1997-08-28 | 1999-03-04 | Hoechst Ag | Sphärische lineare Polysaccharide enthaltende Mikropartikel |
AU1786799A (en) * | 1997-12-18 | 1999-07-05 | Instituut Voor Agrotechnologisch Onderzoek (Ato-Dlo) | Composition for the controlled release of active compounds |
DE19860373B4 (de) * | 1998-12-28 | 2004-02-19 | Celanese Ventures Gmbh | Mundpflegemittel und Verwendung von sphärischen Mikropartikeln |
WO2005005484A1 (ja) | 2003-07-11 | 2005-01-20 | Asahi Kasei Chemicals Corporation | 機能性澱粉粉末 |
WO2006082968A1 (ja) * | 2005-02-07 | 2006-08-10 | Ezaki Glico Co., Ltd. | α-1,4-グルカンを含有する吸着剤およびその製造方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3493652A (en) * | 1962-09-14 | 1970-02-03 | Charles W Hartman | Controlled release medicament |
JPS63104925A (ja) * | 1986-10-22 | 1988-05-10 | Tokyo Tanabe Co Ltd | 胆汁酸固形製剤 |
WO1989000045A1 (en) * | 1987-06-30 | 1989-01-12 | Riker Laboratories, Incorporated | Pellets with enzymatically controlled drug release |
WO1989000601A1 (en) * | 1987-07-10 | 1989-01-26 | The United States Of America, As Represented By Th | Starch encapsulation of biocontrol agents |
-
1992
- 1992-07-03 NL NL9201196A patent/NL9201196A/nl not_active Application Discontinuation
-
1993
- 1993-07-02 AT AT93916290T patent/ATE145821T1/de not_active IP Right Cessation
- 1993-07-02 CA CA002139493A patent/CA2139493A1/en not_active Abandoned
- 1993-07-02 WO PCT/NL1993/000138 patent/WO1994001091A1/en active IP Right Grant
- 1993-07-02 EP EP93916290A patent/EP0648115B1/en not_active Expired - Lifetime
- 1993-07-02 AU AU45892/93A patent/AU677591B2/en not_active Ceased
- 1993-07-02 ES ES93916290T patent/ES2096934T3/es not_active Expired - Lifetime
- 1993-07-02 US US08/362,442 patent/US5629018A/en not_active Expired - Fee Related
- 1993-07-02 JP JP6503184A patent/JPH07508532A/ja active Pending
- 1993-07-02 DK DK93916290.5T patent/DK0648115T3/da active
- 1993-07-02 DE DE69306390T patent/DE69306390T2/de not_active Expired - Fee Related
-
1997
- 1997-02-26 GR GR970400332T patent/GR3022646T3/el unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3493652A (en) * | 1962-09-14 | 1970-02-03 | Charles W Hartman | Controlled release medicament |
JPS63104925A (ja) * | 1986-10-22 | 1988-05-10 | Tokyo Tanabe Co Ltd | 胆汁酸固形製剤 |
WO1989000045A1 (en) * | 1987-06-30 | 1989-01-12 | Riker Laboratories, Incorporated | Pellets with enzymatically controlled drug release |
WO1989000601A1 (en) * | 1987-07-10 | 1989-01-26 | The United States Of America, As Represented By Th | Starch encapsulation of biocontrol agents |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5885615A (en) * | 1996-04-10 | 1999-03-23 | Labopharm Inc. | Pharmaceutical controlled release tablets containing a carrier made of cross-linked amylose and hydroxypropylmethylcellulose |
US20030117171A1 (en) * | 2001-12-20 | 2003-06-26 | Fujitsu Limited | Input/output buffer circuit |
US20030215561A1 (en) * | 2002-05-14 | 2003-11-20 | Yong-Cheng Shi | Resistant starch prepared by isoamylase debranching of low amylose starch |
US20030215562A1 (en) * | 2002-05-14 | 2003-11-20 | Yong-Cheng Shi | Slowly digestible starch product |
US20030219520A1 (en) * | 2002-05-14 | 2003-11-27 | Yong-Cheng Shi | Slowly digestible starch product |
US6890571B2 (en) | 2002-05-14 | 2005-05-10 | National Starch And Chemical Investment Holding Corporation | Slowly digestible starch product |
US6929817B2 (en) | 2002-05-14 | 2005-08-16 | National Starch & Chemical Investment Holding Corporation | Slowly digestible starch product |
US7081261B2 (en) * | 2002-05-14 | 2006-07-25 | National Starch And Chemical Investment Holding Corporation | Resistant starch prepared by isoamylase debranching of low amylose starch |
AU2003204157B2 (en) * | 2002-05-14 | 2007-08-30 | Brunob Ii B.V. | Resistant starch prepared by isoamylase debranching of low amylose starch |
US20050033157A1 (en) * | 2003-07-25 | 2005-02-10 | Klein Dean A. | Multi-modality marking material and method |
US20070071810A1 (en) * | 2003-08-26 | 2007-03-29 | Kenichi Kudo | Additive for tablets |
Also Published As
Publication number | Publication date |
---|---|
AU4589293A (en) | 1994-01-31 |
DE69306390D1 (de) | 1997-01-16 |
JPH07508532A (ja) | 1995-09-21 |
GR3022646T3 (en) | 1997-05-31 |
ES2096934T3 (es) | 1997-03-16 |
CA2139493A1 (en) | 1994-01-20 |
WO1994001091A1 (en) | 1994-01-20 |
EP0648115B1 (en) | 1996-12-04 |
EP0648115A1 (en) | 1995-04-19 |
NL9201196A (nl) | 1994-02-01 |
ATE145821T1 (de) | 1996-12-15 |
DE69306390T2 (de) | 1997-06-05 |
AU677591B2 (en) | 1997-05-01 |
DK0648115T3 (da) | 1997-06-02 |
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Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
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